Determination of Ten Nitrosamine Genotoxic Impurities in Telmisartan Tablets by GC-MS/MS

OBJECTIVE To establish a GC-MS/MS method for simultaneous determination of ten nitrosamine genotoxic impurities in telmisartan tablets, including N-nitrosodimethylamine(NDMA),N-nitrosomethylethylamine(NMEA), N-nitrosodiethylamine(NDEA),N-nitroso-N-ethylisopropylamine(NEIPA), N-nitrosodiisopropylamine(NDIPA),N- nitrosodipropylamine(NDPA), N-nitrosodibutylamine(NDBA), N-nitrosopiperidine(NPIP),N-nitrosopyrrolidine(NPYR) and N-nitrosomorphpline (NMOR). METHODS The sample was extracted with methanol. The sample was separated by an Agilent VF-WAXms (30 m×0.25 mm, 1 μm) capillary gas chromatography column, and the multiple reactive ion monitoring(MRM) was selected for the quantitative detection. RESULTS NDMA, NMEA, NDEA, NEIPA, NDIPA, NDPA, NDBA and NPIP displayed satisfactory linearity(r=1.000 0) over the concentration range of 0.2-50 ng·mL^-1. The limits of detection and the limits of quantification were 0.05 ng·mL^-1and 0.2 ng·mL^-1. The average recoveries were 103%(RSD=9.2%, n=9), 108%(RSD=6.1%, n=9), 107%(RSD=5.3%, n=9), 106%(RSD=3.9%, n=9), 102%(RSD=5.0%, n=9), 99%(RSD=6.9%, n=9), 97%(RSD=8.6%, n=9), 101%(RSD=4.4%, n=9). NPYR and NMOR displayed satisfactory linearity(r=1.000 0) over the concentration range of 1.0-50 ng·mL^-1. The limits of detection and the limits of quantification were 0.4 ng·mL^-1 and 1.0 ng·mL^-1. The average recoveries were 95%(RSD=6.4%, n=9), 103%(RSD=6.1%, n=9). The 254 batches of telmisartan tablets were analyzed by this method, and NDMA was detected in 12 batches. The remaining nine impurities were not detected in 254 batches of sample. CONCLUSION The method is simple, sensitive with strong specificity. It is suitable for the detection of NDMA, NMEA, NDEA, NEIPA, NDIPA, NDPA, NDBA, NPIP, NPYR and NMOR in telmisartan tablets and other preparations.